Glutamatergic neurotransmission in schizophrenia: A systematic review and quantitative synthesis of proton magnetic resonance spectroscopy studies across schizophrenia spectrum disorders

Abstract

Objective: Studies using proton magnetic resonance spectroscopy reveal substantial inconsistencies in the levels of brain glutamate, glutamine and glutamate + glutamine across schizophrenia spectrum disorders. This systematic review employs qualitative and quantitative methods to analyse the patterns and relationships between glutamatergic metabolites, schizophrenia spectrum disorders and brain regions. Methods: A literature search was conducted using various databases with keywords including glutamate, glutamine, schizophrenia, psychosis and proton magnetic resonance spectroscopy. Inclusion criteria were limited to case-control studies that reported glutamatergic metabolite levels in adult patients with a schizophrenia spectrum disorder diagnosis – i.e. first-episode psychosis, schizophrenia, treatment-resistant schizophrenia and/or ultra-treatment-resistant schizophrenia – using proton magnetic resonance spectroscopy at 3 T or above. Pooled study data were synthesized and analysed. Results: A total of 92 studies met the inclusion criteria, including 2721 healthy controls and 2822 schizophrenia spectrum disorder participants. Glu levels were higher in the basal ganglia, frontal cortex and medial prefrontal of first-episode psychosis participants, contrasting overall lower levels in schizophrenia participants. For Gln, strong differences in metabolite levels were evident in the basal ganglia, dorsolateral prefrontal cortex and frontal cortex, with first-episode psychosis showing significantly higher levels in the basal ganglia. In glutamate + glutamine, higher metabolite levels were found across schizophrenia spectrum disorder groups, particularly in the basal ganglia and dorsolateral prefrontal cortex of treatment-resistant schizophrenia participants. Significant relationships were found between metabolite levels and medication status, clinical measures and methodological variables. Conclusion: The review highlights abnormal glutamatergic metabolite levels throughout schizophrenia spectrum disorders and in specific brain regions. The review underscores the importance of standardized future research assessing glutamatergic metabolites using proton magnetic resonance spectroscopy due to considerable literature heterogeneity.